Abstract
Meteorin‐like (metrnl) is a recently identified adipomyokine that beneficially affects glucose metabolism; however, its underlying mechanism of action is not completely understood. We here show that the level of metrnl increases in vitro under electrical pulse stimulation and in vivo in exercised mice, suggesting that metrnl is secreted during muscle contractions. In addition, metrnl increases glucose uptake via the calcium‐dependent AMPKα2 pathway in skeletal muscle cells and increases the phosphorylation of HDAC5, a transcriptional repressor of GLUT4, in an AMPKα2‐dependent manner. Phosphorylated HDAC5 interacts with 14‐3‐3 proteins and sequesters them in the cytoplasm, resulting in the activation of GLUT4 transcription. An intraperitoneal injection of recombinant metrnl improved glucose tolerance in mice with high‐fat‐diet‐induced obesity or type 2 diabetes, but not in AMPK β1β2 muscle‐specific null mice. Metrnl improves glucose metabolism via AMPKα2 and is a promising therapeutic candidate for glucose‐related diseases such as type 2 diabetes.
Highlights
Exercise has the potential to protect against metabolic disease, cardiovascular disease, cancer, and dementia [1]
To further understand the effect of metrnl on electrical pulse stimulation (EPS)-induced AMPKa1/2 phosphorylation, we used siRNA-mediated downregulation of metrnl to block the phosphorylation of AMPKa1/2 after acute EPS (Fig. 1F)
In addition to the expression of metrnl, the phosphorylation of AMPKa1/2 and TBC1 domain family member 1 (TBC1D1) increased in the quadriceps femoris muscles of the chronic exercised mice (Fig. 1J)
Summary
Exercise has the potential to protect against metabolic disease, cardiovascular disease, cancer, and dementia [1]. Skeletal muscle cells secrete various proteins called myokines that elicit responses in an auto-, para-, or endocrine manner [2,3]. The FEBS Journal 287 (2020) 2087–2104 a 2020 The Authors. Adipose tissue is an endocrine organ that releases various adipokines to control systemic metabolism and energy homeostasis [9,10]. Skeletal muscle contractionregulated myokines are secreted by adipocytes and are called adipomyokines; they are associated with beneficial, exercise-induced metabolic effects [11,12,13]. We have previously analyzed the role of the adipomyokines irisin [14], fstl-1 [15], resistin [16], and visfatin [17], which perform various functions in different organs
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